Process for preparing aminoarylacetylenes

ABSTRACT

This invention provides a process for preparing aminoarylacetylenes comprising reacting a N-arylmethylidene aminoarylhalide with a terminal acetylene in the presence of a base and a catalyst system comprising a palladium catalyst and a cuprous salt to produce a novel N-arylmethylidene aminoarylacetylene, and hydrolyzing the N-arylmethylidene aminoarylacetylene to the aminoarylacetylene. In one embodiment, the invention provides a process for preparing aminophenylacetylenes comprising reacting a N-benzylidene aminophenylhalide with a terminal acetylene in the presence of a base and the catalyst system to produce a novel N-benzylidene aminophenylacetylene, and hydrolyzing the N-benzylidene aminophenylacetylene to the aminophenylacetylene.

FIELD OF THE INVENTION

This invention relates generally to preparing aminoarylacetylenes. Morespecifically, it relates to preparing aminoarylacetylenes fromaminoarylhalides and terminal acetylenes and to novel compounds whichare useful in their preparation. Aminophenylacetylenes are valuable asprecursors to pharmaceutically active compounds and to acetyleneterminated polymers. In particular, 3-aminophenylacetylene is used as anend-capping agent for high performance polyimide resins.

BACKGROUND OF THE INVENTION

Sabourin, Prepr. Div. Pet. Chem., Am. Chem. Soc., vol. 24, pp. 233-239discloses the preparation of 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol (anaminophenylacetylene) and 3-aminophenylacetylene in two and three steps,respectively, from 3-bromonitrobenzene and 2-methyl-3-butyn-2-ol. In thefirst step, 3-bromonitrobenzene and 2-methyl-3-butyn-2-ol were reactedin the presence of a catalyst system of bis(triphenylphosphine)palladiumdichloride, additional triphenylphosphine, and cuprous iodide intriethylamine solvent at the reflux temperature to obtain2-methyl-4-(3-nitrophenyl)-3-butyn-2-ol. In the second step, thisnitrophenylacetylene was hydrogenated in isopropanol in the presence ofa Ru/Al₂O₃ catalyst to obtain 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol.This reference states that is essential to stop the hydrogenationreaction at the stoichiometric point because reduction of the triplebond ensues. In the third step, this aminophenylacetylene was heated intoluene in the presence of sodium hydroxide pellets, with removal of theacetone co-product by distillation, to obtain 3-aminophenylacetylene.

This reference also discloses an attempt to similarly react3-bromoaniline, instead of 3-bromonitrobenzene, with2-methyl-3-butyn-2-ol to obtain 2-methyl-4-(3-aminophenyl)-3-butyn-2-oldirectly, and reports that 3-bromoaniline failed to react at anyappreciable rate at temperatures up to ca. 100 ° C.

U.S. Pat. Nos. 4,128,588 and 4,204,078 (each also from the same Sabourinas inventor, with Selwitz) also discloses this preparation of2-methyl-4-(3-nitrophenyl)-3-butyn-2-ol from 3-bromonitrobenzene and2-methyl-3-butyn-2-ol. U.S. Pat. No. 4,139,561 and J. Org. Chem., vol.44 (1979), pp. 1223-1236 (both Onopchenko as well as the same Sabourinand Selwitz) also discloses the preparation of2-methyl-4-(3-aminophenyl)-3-butyn-2-ol from2-methyl-4-(3-nitrophenyl)-3-butyn-2-ol by hydrogenation with aruthenium catalyst, and its subsequent conversion to3-aminophenylacetylene. Both the patent and journal disclosureshighlight the difficult challenge of selectively hydrogenating the nitrogroup in the presence of the acetylene group. Subsequent U.S. Pat. Nos.4,215,226; 4,216,341; 4,219,679 and a publication J. Org. Chem., vol. 44(1979), pp.3671-3674 from Onopchenko, Sabourin, and Selwitz disclosehydrogenations of 2-methyl-4-(3-nitrophenyl)-3-butyn-2-ol to2-methyl-4-(3-aminophenyl)-3-butyn-2-ol using other hydrogenationcatalysts.

Synlett, 1995, pp.1115-1116 discloses this preparation of2-methyl-4-(4-nitrophenyl)-3-butyn-2-ol from 4-bromonitrobenzene and2-methyl-3-butyn-2-ol in high yield using a catalyst system comprisingpalladium on carbon, triphenylphosphine, and cuprous iodide in thepresence of 2.5 equivalents of potassium carbonate in 1:11,2-dimethoxyethane:water at 80 ° C. This reference also discloses thepreparation of 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol in 78% isolatedyield from 3-iodoaniline (in place of 4-bromonitrobenzene) using thesame system and the same conditions. The reference does not disclose anyattempt to similarly react 3-bromoaniline.

OBJECTS OF THE INVENTION

The object of this invention is to provide an economically preferable,effective and efficient process for the preparationaminophenylacetylenes. A further object of this invention is to providea process for the preparation of aminophenylacetylenes that avoids theinherent challenge of selectively hydrogenating a nitro group in thepresence of an acetylene group. Another object of this invention is toprovide a process for the preparation of aminophenylacetylenes fromaminophenylhalides. The present invention is directed towards one ormore of the above objects. Other objects and advantages will becomeapparent to persons skilled in the art and familiar with the backgroundreferences from a careful reading of this specification.

SUMMARY OF THE INVENTION

In its most general terms, the present invention provides a process forpreparing aminoarylacetylenes comprising reacting an N-arylmethylideneaminoarylhalide with a terminal acetylene in the presence of a base anda catalyst system comprising a palladium catalyst and a cuprous salt toproduce a novel N-arylmethylidene aminoarylacetylene. TheN-arylmethylidene aminoarylacetylene may be hydrolyzed to remove theN-arylmethylidene group and provide the aminoarylacetylene. The presentinvention thereby provides a practical process for preparing anaminophenylacetylene comprising reacting a N-benzylideneaminophenylhalide with a terminal acetylene in the presence of a baseand a catalyst system comprising a palladium catalyst and a cuprous saltto produce a novel N-benzylidene aminophenylacetylene, and hydrolyzingthe N-benzylidene aminophenylacetylene to the aminophenylacetylene.N-benzylidene aminophenylhalides can be readily prepared from thecorresponding benzaldehyde and the corresponding aminophenylhalide bymethods known in the art, typically in the presence of an acid catalyst.In certain embodiments of the present invention, the N-benzylideneaminophenylhalide is provided in the reaction by the benzaldehyde, theaminophenylhalide, and an acid catalyst. The invention thereby providesa process for the preparation of aminophenylacetylenes fromaminophenylhalides that avoids the inherent challenge of selectivelyhydrogenating a nitrophenylacetylene to an aminophenylacetylene.

From experiments using a substoichiometric amount of benzaldehyderelative to the aminophenylhalide, it was surprisingly discovered thatthe remaining free aminophenylhalide in the mixture with the resultingN-benzylidene aminophenylhalide also reacts, providing a mixture of theaminophenylacetylene and the N-benzylidene aminophenylacetylene.Apparently, the substoichiometric amount of the benzylidene groupcatalyzes the conversion of aminophenylhalide to theaminophenylacetylene. While not intending to be bound by theory, thiscan be explained by the benzylidene group being transferred, during thereaction, from the initial product, the N-benzylideneaminophenylacetylene, to the unreacted free aminophenylhalide,converting it to the more reactive N-benzylidene aminophenylhalide.

In one preferred embodiment, the present invention provides a processfor the preparation of 3-aminophenylacetylene carbinols from3-aminophenylhalides comprising reacting a N-benzylidene derivative ofthe 3-aminophenylhalide with a alpha-hydroxy terminal acetylene in thepresence of an amine base and a catalyst system comprising a palladiumcatalyst comprising a phosphorus ligand and a cuprous halide, andhydrolyzing the resulting novel N-benzylidene 3-aminophenylacetylenecarbinol to the 3-aminophenylacetylene carbinol. Optionally, a mixtureof the 3-aminophenylhalide and the N-benzylidene 3-aminophenylhalide isreacted to provide a mixture of the 3-aminophenylacetylene carbinol andthe corresponding N-benzylidene aminophenylacetylene carbinol.3-amino-phenylacetylene carbinols may be converted to3-aminophenylacetylene by methods known in the art. The inventionthereby provides an efficient process for the preparation of3-aminophenylacetylene from 3-aminophenylhalides.

DETAILED DESCRIPTION OF THE INVENTION

Suitable starting materials and intermediates for the preparation ofaminoarylacetylenes by the present invention are aminoarylhalides ingeneral, arylcarboxaldehydes in general, terminal acetylenes in general,N-arylmethylidene aminoarylhalides in general, and N-arylmethylideneaminoarylacetylenes in general. The N-arylmethylidene aminoarylhalideand the N-arylmethylidene aminoarylacetylene may be cis isomers or transisomers, or mixtures thereof, about the carbon-nitrogen double bond.

Suitable aminoaryl groups for the aminoarylhalide, the N-arylmethylideneaminoarylhalide, the N-arylmethylidene aminoarylacetylene, and theaminoarylacetylene include those in which the aryl ring system is acarbocyclic aromatic ring system, having only carbon atoms in the ringsystem, and those in which the aromatic ring system is a heterocyclicaromatic ring system, having one or more heteroatoms in the ring system.Typical carbocyclic aromatic ring systems in the aminoaryl group have6-14 carbon atoms in the aromatic ring system. Preferred carbocyclicaromatic ring systems are phenyl and substituted phenyl groups. Suitableheterocyclic aromatic ring systems in the aminoaryl group have 5-13atoms in the aromatic ring system which comprises carbon atoms and oneor more heteroatoms. Preferred heteroatoms are oxygen, sulfur, andnitrogen. Typical heterocyclic aromatic ring systems have 5 or 6 atomsin an aromatic ring comprising one or more heteroatoms selected from thegroup oxygen, sulfur, and nitrogen, benz-fused derivatives thereof, andsubstituted derivatives thereof. Examples of preferred heterocyclicaromatic ring systems in the aminoaryl group include pyridyl, furyl,thienyl, pyrrolyl, their benz-fused derivatives quinolinyl,isoquinolinyl, benzfuryl, benzothienyl, indolyl, isoindolyl, andsubstituted derivatives thereof.

Suitable aryl groups for the arylmethylidene group of thearylcarboxaldehyde, the N-arylmethylidene aminoarylhalide, and theN-arylmethylidene aminoarylacetylene include those having the aromaticring systems described above as suitable for the aminoaryl group. (Anarylcarboxaldehyde is an arylmethylidene oxide. For example,benzaldehyde is benzylidene oxide and is phenylcarboxaldehyde and isphenylmethylidene oxide.) The aromatic ring system in thearylmethylidene group may be the same or different from the aromaticring system in the aminoaryl group.

For the preparation of aminophenylacetylenes via N-benzylideneaminophenylhalides, suitable starting materials and intermediates areaminophenylhalides in general, benzaldehydes in general, terminalacetylenes in general, N-benzylidene aminophenylhalides in general, andN-benzylidene aminophenylacetylenes in general. Suitableaminophenylhalides, benzaldehydes, terminal acetylenes, N-benzylideneaminophenylhalides, and N-benzylidene aminophenylacetylenes includethose having the structural formulas I, II, III, IV, and V,respectively. The aminophenylacetylenes prepared from these suitablestarting materials and intermediates have the structural formula VI.

X in formulas I and IV is a halogen substituent selected from the groupconsisting of chloro, bromo, and iodo, preferably selected from thegroup bromo and iodo, and most preferably bromo.

Y in formulas I, IV, V and VI is a substituent selected fromsubstituents that do not interfere with the reaction chemistry of theinvention. These are known to persons skilled in the art and can bedetermined by routine experimentation. Examples of suitable substituentsinclude fluoro, chloro (provided X is bromo or iodo), alkyl (preferablyC₁-C₁₂), alkenyl (preferably C₁-C₁₂), alkynyl (preferably C₁-C₁₂),alkoxy (preferably C₁-C₁₂), acyloxy (preferably C₁-C₁₂), aryl, aryloxy,heteroaryl, OH, NO₂, CN, COOH, SO₂R, SOR, NH₂, NH-alkyl (preferablyC₁-C₁₂), N-dialkyl (preferably C₁-C₁₂), trihalomethyl, NHCO-alkyl(preferably C₁-C₈), CONH-alkyl (preferably C₁-C₄), CON-dialkyl(preferably C₁-C₄), COO-alkyl (preferably C₁-C₁₂), CONH₂, CO-alkyl(preferably C₁-C₁₂), NHCOH, NHCOO-alkyl (preferably C₁-C₈), CO-aryl,COO-aryl, CHCHCO₂-alkyl (preferably C₁-C₁₂), CHCHCO₂H, PO-diaryl, andPO-dialkyl (preferably C₁-C₈).

The subscript n in the formulas I, II, IV, V, and VI is an integer from0 to 4, preferably 0 or 1, and most preferably 0. When n=0, nosubstituent Y is present in the formula. When n is greater than 1, the Ysubstituents may be the same or different and are selected independentlyof each other.

Z in formulas II, IV, and V is defined as for Y above. The subscript mis an integer from 0 to 5, preferably 0 or 1, and most preferably 0.When m=0, no substituent Z is present in the formula. When m is greaterthan 1, the Z substituents may be the same or different and are selectedindependently of each other.

The N-benzylidene aminophenylhalides and N-benzylideneaminophenylacetylenes can be trans isomers (as shown in formulas IV andV) or cis isomers, or mixtures thereof, about the carbon-nitrogen doublebond.

R in formulas III, V, and VI is hydrogen or any substituent that doesnot interfere with the reaction chemistry of the invention. These areknown to persons skilled in the art and can be determined by routineexperimentation.

Examples of suitable substituents include alkyl (preferably C₁-C₁₂),alkenyl (preferably C₁-C₁₂), alkynyl (preferably C₁-C₁₂), alkoxy(preferably C₁-C₁₂), acyloxy (preferably C₁-C₁₂), aryl, aryloxy,heteroaryl, NH-alkyl (preferably C₁-C₁₂), N-dialkyl (preferably C₁-C₁₂),trihalomethyl, NHCO-alkyl (preferably C₁-C₈), CONH-alkyl (preferablyC₁-C₄), CON-dialkyl (preferably C₁-C₄), COO-alkyl (preferably C₁-C₁₂),CONH₂, CO-alkyl (preferably C₁-C₁₂), NHCOH, NHCOO-alkyl (preferablyC₁-C₈), CO-aryl, COO-aryl, CHCHCO₂-alkyl (preferably C₁-C₁₂), andhydroxyalkyl (preferably C₁-C₁₂).

In a preferred embodiment, a N-benzylidene aminophenylhalide, optionallyin mixture with additional aminophenylhalide, is reacted with aalpha-hydroxy terminal acetylene to provide the N-benzylideneaminophenylacetylene carbinol and, ultimately, the aminophenylacetylenecarbinol. R in the alpha-hydroxy terminal acetylene, the N-benzylideneaminophenylacetylene carbinol and the aminophenylacetylene carbinol is aalpha-hydroxyalkyl group of the formula —C(OH)R′R″, as shown in formulasVII, VIII, and IX, respectively.

Y, n, Z and m in formulas VIII and IX are defined as above.

R′ and R″ in formulas VII, VIII, and IX can be the same or different andare defined as for R, above. Preferred R′ and R″ are independentlyselected from the group consisting of hydrogen, lower alkyl groupshaving from 1 to 4 carbon atoms, phenyl, substituted phenyl; or R′ andR″ when taken together with the carbon bearing the hydroxyl group form asaturated cycloalkyl group, preferably a cyclohexyl or cylopentyl group.

The preparation of the alpha-hydroxy terminal acetylenes is well knownin the art. For example, acetylene can be reacted with acetone to form2-methyl-3-butyn-2-ol (also known as acetylene dimethylcarbinol), whichis a preferred alpha-hydroxy terminal acetylene for use in the processof this invention. Other suitable alpha-hydroxy terminal acetylenesinclude 3-methyl-1-pentyn-3-ol, 3-ethyl-1-pentyn-3-ol,2-phenyl-3-butyn-2-ol, 1-ethynylcyclohexanol, and 1-ethynlcyclopentanol.

In the following detailed description of the process, theaminophenylhalide, the benzaldehyde, the N-benzylideneaminophenylhalide, the N-benzylidene aminophenylacetylene, and theaminophenylacetylene are used, as preferred embodiments, to describe theprocess for aminoarylhalides in general, arylcarboxaldehydes in general,N-arylmethylidene aminoarylhalides in general, N-arylmethylideneaminoarylacetylenes in general, and aminoarylacetylenes in general,respectively.

The N-benzylidene aminophenylhalides can be prepared by methods known inthe art for preparing imines from anilines and benzaldehydes, typicallyin the presence of an acid catalyst. The N-benzylidene aminophenylhalidecan be provided preformed to the reaction or can be prepared in solutionfor the reaction from the benzaldehyde, the aminophenylhalide, and anacid catalyst. The nature and amount of the acid catalyst is notcritical provided it is effective to produce the N-benzylideneaminophenylhalides and does not interfere with the process to form theaminophenylacetylene, which can be determined by routineexperimentation. Benzaldehydes from commercial sources often contain thecorresponding benzoic acid as an impurity, and in many cases, thisbenzoic acid is all the acid that is needed to catalyze the formation ofthe N-benzylidene aminophenylhalides. Other carboxylic acids (e.g.acetic acid) also provide effective acid catalysts. Hydrohalic acids andamine hydrohalides may also be used. Solid acids, acid resins forexample, may also be used.

When formed in the solution for reaction, the mole ratio of benzaldehydeto the aminophenylhalide is typically in the range 0.01:1 to 1.1:1,preferably in the range 0.1:1 and 1.0:1. When a mole ratio of 1.0:1 orgreater is used, essentially all of the aminophenylhalide is convertedto the N-benzylidene aminophenylhalide. When a mole ratio of less than1.0:1 is used, a mixture of N-benzylidene aminophenylhalide and freeaminophenylhalide is provided. Mixtures of N-benzylideneaminophenylhalide and free aminophenylhalide can also be provided usingpreformed N-benzylidene aminophenylhalide. The mole ratio ofN-benzylidene aminophenylhalide to free aminophenylhalide in suchmixtures, whether made using preformed N-benzylidene aminophenylhalideor made using the benzaldehyde is typically in the range 0.01:1 to0.99:1, preferably in the range 0.1:1 to 0.9:1. As used herein, the term“aminophenylhalide reactant” refers to the N-benzylideneaminophenylhalide in combination with any free aminophenylhalide inmixture with it.

The ratio of the aminophenylhalide reactant to the terminal acetylene isnot critical. Either reactant may be the limiting reactant and thischoice can respond to other considerations, such as which is the morecostly reactant to provide and which is more readily separated orremoved to an acceptable level from the product. Generally the moleratio of aminophenylhalide reactant to terminal acetylene is in therange 0.5:1 to 2:1. In typical embodiments, this ratio is in the range1:1 to 1.5:1.

The reaction of the aminophenylhalide reactant with the terminalacetylene occurs in the presence of a base according to the followinggeneral reaction equation:

wherein Ar is the aminophenyl of the aminophenylhalide reactant, and Xand R are as defined above. The identity of the base is not criticalprovided it is effective in the reaction and does not interfere with thereaction, which can be determined by routine experimentation. Suitablebases include amine bases, carboxylate salts, carbonate salts, andbicarbonate salts. Secondary and tertiary amine bases are preferred.Particularly preferred are dialkyl and trialkyl amines having thegeneral formula NR^(a)R^(b)R^(c), wherein R^(a), R^(b), and R^(c) areindependently selected from the group consisting of hydrogen and loweralkyl groups having from 1 to 4 carbons; or where two of R^(a), R^(b),and R^(c) when taken together with the nitrogen form a heterocyclicamine; with the proviso that no more than one of R^(a), R^(b), and R^(c)is hydrogen. Illustrative examples of such preferred amine bases includedimethylamine, trimethylamine, diethylamine, triethylamine,dibutylamine, tributylamine, and N-methylpiperidine. Most preferred arethe trialkyl amines. Related amine bases that do not fit this formulaprecisely, such as N-methylmorpholine, N,N-dimethylaniline, andN,N-dimethylaminopyridine are also suitable. A combination of a solublebase (e.g. an amine base) and an insoluble base (e.g. a carbonate salt)may also be used.

The mole ratio of the base to the limiting reactant, whether theaminophenylhalide reactant or the terminal acetylene is typically atleast 1.0. Higher ratios of base to the reactants are suitable. Thepreferred amine bases may be conveniently used as solvent for thereaction.

Suitable palladium catalysts include those provided by palladiumcompounds and salts, in particular palladium(0) compounds andpalladium(II) compounds and salts. Preferably, the catalyst alsocomprises a ligand. Suitable ligands include monodentate and bidentateligands comprising nitrogen or phosphorus as ligating atom. Preferredligands are triorganophosphine, triorganophosphite, and aromaticnitrogen heterocycle ligands. Examples of preferred ligands includetriarylphosphines (e.g. triphenylphosphine), bidentatebis(diarylphosphino) compounds (e.g.1,1′-bis-(diphenylphosphino)butane), trialkylphosphites (e.g.triisopropylphosphite), and pyridine-type ligands (e.g. pyridine,bipyridine). Particularly preferred ligands are trioganophosphineshaving the general formula PR^(d)R^(e)R^(f), wherein R^(d), R^(e), andR^(f) are independently selected from the group consisting of alkylgroups having from 1 to 6 carbon atoms, phenyl, and substituted phenylgroups. The substituents on the phenyl groups can include alkyl groupshaving from 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbonatoms, and halogen. Triphenylphosphine is a frequently used preferredligand.

Suitable and optimal ratios of the ligand to palladium depend on anumber of other parameters, including the identity of the ligand, theconcentration of the palladium catalyst, the reaction temperature, thereactivity of the reactants, the solvent, and the like, and can bereadily determined by routine experimentation. Typically the mole ratioof the ligand to palladium is in the range of 1:1 to 100:1, preferablyin the range 2:1 to 50:1, and most preferably in the range 4:1 to 20:1.In certain embodiments, improved conversion of the aminophenylhalidereactant and improved yield of the aminophenylacetylene is obtained byproviding an amount of ligand in the reaction mixture in excess of themaximum mole ratio (4:1) that can be bound to the palladium.

The active palladium catalyst may be prepared in advance of itsintroduction to the reaction mixture, or may be generated in thereaction mixture. It is believed that the active catalyst in thereaction is a palladium(0) compound. The active palladium catalyst maybe provided by a preformed ligated palladium(0) compound (e.g.tetrakis(triphenylphosphine)palladium(0)), or may be provided bycombining in solution, either ex situ or in situ to the reactionmixture, a suitable ligand with a suitable palladium(0) compound (e.g.tris(dibenzylideneacetone)palladium(0)). When the catalyst is providedby a palladium(II) compound or salt, the active catalyst is provided byits reduction either ex situ or in situ to the reaction mixture.Generally, the other components of the reaction mixture (e.g. an aminebase) is capable of reducing the palladium(II) to generate the activecatalyst in situ. This can be determined by routine experimentation.Suitable reductants for ex situ generation of the active catalyst fromand palladium(II) sources are known in the art and includeorganomagnesium halide reagents (e.g. methylmagnesium halide) andvarious hydride reagents (e.g. sodium bis(2-methoxyethoxy)aluminumdihydride). Preferably the palladium(II) is combined with ligand priorto its reduction. The palladium(II) may be provided as a preformedligated palladium(II) compound (e.g.dichlorobis(triphenylphosphine)palladium(II)) or may be provided bycombining in solution a suitable ligand with a suitable palladium(II)compound (e.g. dichlorobis(acetonitrile)palladium(II)) or palladium(II)salt. Suitable palladium(II) salts include the salts having the generalformula PdA₂, wherein A is an inorganic or organic salt anion. Theidentity of the anion A is not critical but it must not interfere withthe reaction, which can be determined by routine experimentation.Preferred palladium(II) salts include the chlorides, bromides,carboxylates (e.g. formate, acetate, stearate) and acetylacetonates.Particularly preferred are palladium diacetate and palladium dichloride.

The amount of palladium catalyst is not critical, but should be acatalytic mole ratio less than about 1:10 to the aminophenylhalidereactant, and preferably less than about 1:100. The minimum amount ofpalladium catalyst depends on other parameters, including the identityof the ligand, the concentration of the ligand, the reactiontemperature, the reactivity of the specific reactants, how much of theaminophenylhalide reactant is the N-benzylidene aminophenylhalide, theconcentration of the reactants, the solvent, and the maximum timeallowed for completion of the reaction, and can be readily determined byroutine experimentation. In typical embodiments, a suitable mole ratioof the palladium catalyst to the aminophenylhalide reactant is in therange of 1:10,000 to 1:100, preferably in the range 1:5000 to 1:500.

Suitable cuprous salts include those having the general formula CuA,wherein A is defined as above, but is independently selected. Preferredcuprous salts are the cuprous halides. Cuprous iodide is particularlypreferred. The amount of cuprous salt is not critical, but should be acatalytic mole ratio less than about 1:10 to the aminophenylhalidereactant. The minimum amount of cuprous salt depends on otherparameters, like those listed above for the amount of palladiumcatalyst. In typical embodiments, a suitable mole ratio of cuprous saltto palladium catalyst is in the range of 1:1 to 100:1, preferably in therange of 5:1 to 25:1.

The reaction of the aminophenylhalide reactant with the terminalacetylene may be conducted without solvent, with an excess of amine baseas solvent, with an additional solvent that is reaction-inert, or with amixture of excess amine base and a solvent that is reaction inert. Byreaction-inert solvent is meant a solvent system which does not reactwith the reactants or products of the reaction, or react unfavorablywith the catalyst. The term solvent system is used to indicate that asingle solvent or a mixture of two or more solvents can be used.Representative solvents are aromatic hydrocarbons such as benzene,toluene, xylene; aliphatic hydrocarbons such as pentane, hexane,heptane; acetonitrile; dialkyl ethers; cyclic ethers, polar aproticsolvents such as dimethylformamide, dimethylacetamide,N-methylpyrollidone, and sulfolane, chlorinated hydrocarbons such asmethylene chloride, dichloroethylene, carbon tetrachloride, andchloroform, and mixtures thereof The solvent system used need not bringabout complete solution of the reactants. Preferred solvents include theamine base and mixtures of the amine base and a hydrocarbon solvent.

The reaction temperature is not critical, but is preferably sufficientfor the reaction to proceed at a practical rate. Suitable and optimalreaction temperatures depend on a number of other parameters, includingthe reactivity of the specific catalyst system, the concentration of thecatalyst components, the concentrations and reactivities of the specificreactants, and the solvent, and can be readily determined by routineexperimentation. In typical embodiments, the reaction is conducted at atemperature in the range from about 20° C. to 200° C., preferably fromabout 50° C. to 120° C. It is often convenient to conduct the reactionat the reflux temperature of the reaction mixture.

The order of addition of the reaction components is not critical. Allthe reaction components can be added prior to any heating to thereaction temperature, or one or more components may be added when theother components have be brought to the desired reaction temperature.The preferred order of addition for any specific embodiment can bedetermined by routine experimentation with a view towards both reactionperformance and chemical engineering considerations.

N-benzylidene aminophenylacetylene formed by the reaction may behydrolyzed to the aminophenylacetylene by methods known in the art forthe hydrolysis of C,N-diaryl imines in general. Typically this isaccomplished by treating the imine with water and an acid. Thehydrolysis of the N-benzylidene aminophenylacetylene can be conducted atany point in the process subsequent to the conversion of theaminophenylhalide reactant being judged suitably complete. Water andacid can be added to the converted reaction mixture to effect thehydrolysis prior to any separations. Alternatively, the hydrolysis canconducted later in the separations scheme. Another alternative is toisolate the N-benzylidene aminophenylacetylene, optionally incombination with any free aminophenylacetylene co-product of thereaction, and subsequently subject it to hydrolysis to theaminophenylacetylene.

The N-benzylidene aminophenylacetylene and the aminophenylacetylene caneach be recovered and isolated by known methods.

EXAMPLES OF THE INVENTION

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following specific examples are intended merelyto illustrate the invention and not to limit the scope of the disclosureor the scope of the claims in any way whatsoever.

Example 1

Preparation of 3-(N-benzylidene)aminophenylacetylene dimethylcarbinol: Asolution of equimolar amounts of 3-bromoaniline (1.72 g, 10 mmol) andbenzaldehyde (1.06 g, 10 mmol), and benzoic acid (0.20 g, 1.6 mmol) intriethylamine (5 g) was heated at reflux for 12 hours. The reaction wasessentially complete by thin-layer chromatography (40% ethylacetate/heptane; silica). The ¹H-NMR spectrum of an aliquot showed thepresence of N-benzylidene 3-aminophenylbromide (benzylidenyl protonsinglet at δ8 8.43 (CD₂Cl₂); compared to authentic N-benzylidene anilineat 8.45).

The reaction mixture was cooled and PdCl₂ (2 mg, 0.01 mmol) andtriphenylphosphine (73 mg, 0.28 mmol) were added. The mixture wasdeaerated by bubbling nitrogen. This reaction mixture was heated atreflux for 20 min and then treated with a slurry of CuI (20 mg, 0.1mmol) in 2-methyl-3-butyn-2-ol (1.1 g, 13 mmol). The reaction mixturewas heated at reflux for 12 hours. Thin-layer chromatography (40% ethylacetatelheptane; silica) showed the reaction to be complete.

An aliquot of the reaction mixture was dissolved in CH₂Cl₂/hexane andextracted with water. The organic phase was evaporated under a stream ofnitrogen. The ¹H-NMR spectrum of the resulting oil was consistent withthe benzylidene imine of 3-methyl-4-(3-aminophenyl)-3-butyn-2-ol(N-benzylidene 3-aminophenylacetylene dimethylcarbinol), havingresonances for both the benzylidenyl proton (δ8.46, s, 1H) and thedimethylcarbinol moiety (δ1.60, s, 6H). ¹H-NMR (CD₂Cl₂): δ1.60 (s, 6H),2.5 (brs, 1H), 7.15-7.20 (m, 1H), 7.25-7.49 (m, 3H), 7.45-7.55 (m, 3H),7.88-7.95 (m, 2H), 8.46 (s, 1H).

Another aliquot of the reaction mixture was partitioned between 40%ethyl acetate/heptane and water. The organic phase was analyzed byGC/MS, showing only one major non-solvent peak. The mass spectrum ofthis elute showed a molecular ion (M⁺) of mass 263, consistent withC₁₈H₁₇NO for N-benzylidene 3-aminophenylacetylene dimethylcarbinol.

Another aliquot of the reaction mixture was hydrolyzed to remove theN-benzylidene group by partitioning between 40% ethyl acetate/heptaneand aqueous HCl. The acidic aqueous phase was separated, basified withaqueous sodium hydroxide, and extracted with 40% ethyl acetate/heptane.Thin-layer chromatography of the organic solution showed (vs. authenticstandard) 3-methyl-4-(3-aminophenyl)-3-butyn-2-ol as the majorcomponent.

This example illustrates the process of the present invention wherein aN-benzylidene aminophenylacetylene (N-benzylidene 3-aminophenylacetylenedimethylcarbinol) is prepared by reacting a N-benzylideneaminophenylhalide (N-benzylidene 3-aminophenylbromide), preformed exsitu, with a terminal acetylene (2-methyl-3-butyn-2-ol; also calledacetylene dimethylcarbinol) in the presence of a base (triethylamine)and a catalyst system comprising a palladium catalyst and a cuproussalt.

Example 2

Preparation of 3-aminophenylacetylene dimethylcarbinol: To a nitrogenpurged 250 mL three-neck flask equipped with a mechanical stirrer,reflux condenser and septum inlet was added benzoic acid (300 mg, 2.8mmol) and PdCl₂ (25 mg). Then 3-bromoaniline (25 g, 145 mmol),benzaldehyde (4.6 g, 44 mmol) and triethylamine (80 mL) were charged.The resulting mixture was vacuum deaerated (150 torr; N₂ backfill; 5×)and heated under nitrogen at reflux for one hour to form theN-benzylidene 3-aminophenylbromide.

The resulting mixture was cooled to 50° C. and triphenylphosphine (0.94g in 10 mL triethylamine) was added via syringe. Then2-methyl-3-butyn-2-ol (16 g) was added followed by CuI (0.3 g in 20 mLtriethylamine). The reaction mixture was refluxed for 10 hours. Aftercooling, toluene (20 mL) and water (40 mL) containing 50% sodiumhydroxide (11.6 g) were added. The aqueous phase was separated and theresulting mixture was distilled under vacuum (200 torr) while addingmore toluene (3×, 75 mL). A total of 300 mL of distillate was obtained.The resulting slurry was cooled and treated with HCl (100 mL, containing21 g of 37% HCl). This mixture was stirred for 1 hour at roomtemperature to hydrolyze the N-benzylidene 3-aminophenylacetylenedimethylcarbinol.

The aqueous solution of the product was separated and treated withtoluene (35 mL) and ethyl acetate (30 mL). This mixture was cooled (icebath) and basified with 50% sodium hydroxide (17 g). Some of the aqueousphase was separated and then the mixture was heated to 60° C. Theremaining aqueous phase was separated and more toluene (155 mL) wasadded. This mixture was cooled to crystallize the product. Filtrationand washing with cold toluene and drying in vacuo afforded 19.21 g(75.5%) of 2-methyl-4-(3-amino-phenyl)-3-butyn-2-ol. ¹H-NMR (DMSO-d₆):δ1.44 (s, 6H), 5.14 (brs, 2H), 5.37 (s, 1H), 6.5-6.7 (m, 3H), 6.97 (t,1H, J=7.8 Hz).

This example illustrates the process of the invention wherein a mixtureof an aminophenylhalide and a corresponding N-benzylideneaminophenylhalide, preformed ex situ by reacting the aminophenylhalidewith a substoichiometric amount of a benzaldehyde (0.3 eq in this case),are reacted with a terminal acetylene in the presence of a base and acatalyst system comprising a palladium catalyst and a cuprous salt toprovide a mixture of the aminophenylacetylene and the correspondingN-benzylidene aminophenylacetylene, and hydrolyzing the N-benzylideneaminophenylacetylene in the mixture to the aminophenylacetylene.

Comparative Example

The procedure was the same as in Example 2 using benzaldehyde free ofbenzoic acid, through the steps intended for the ex situ formation ofthe N-benzylidene 3-aminophenylbromide and the catalyzed reaction with2-methyl-3-butyn-2-ol, with the exception that no benzoic acid wasadded. Upon the addition of the CuI, an apparent precipitation of Pd wasobserved (not seen in the procedure of Example 2). After several hoursof reflux no reaction to form an aminophenylacetylene dimethylcarbinol,with or without the N-benzylidene moiety, could be observed bythin-layer chromatography.

Comparison with Examples 2 demonstrates that when the N-benzylideneimine of the aminophenylhalide is not present, in this case because noacid catalyst was provided for its formation from the benzaldehyde, thecatalytic reaction to couple the aminophenylhalide with the terminalacetylene does not readily proceed. It further indicates that, in thepresent invention, the availability of the N-benzylideneaminophenylhalide for reaction serves to stabilize the palladiumcatalyst.

Example 3

Preparation of 3-aminophenylacetylene dimethylcarbinol: A mixture of4-bromoaniline (1.72 g, 10 mmol), benzaldehyde (0.27 g free of benzoicacid, 2.5 mmol), benzoic acid (20 mg, 0.16 mmol), PdCl₂ (2 mg) andtriethylamine (3.5 g) was deaerated by bubbling nitrogen and then heatedto reflux for 30 min. The reaction mixture was cooled to 50° C. andtreated with triphenylphosphine (73 mg in 0.5 g of TEA) followed by2-methyl-3-butyn-2-ol (1.1 g, 13 mmol) and then CuI (20 mg in 1 g TEA).This mixture was heated at reflux for 12 hr. Thin layer chromatographyshowed the reaction to form 3-aminophenylacetylene dimethylcarbinol, inmixture with N-benzylidene 3-aminophenylacetylene dimethylcarbinol, tobe complete.

Comparison to the Comparative Example above demonstrates that theaddition of an acid catalyst (in this case benzoic acid) in order toform the N-benzylidene aminophenylhalide when using benzaldehyde free ofbenzoic acid provides for a successful conversion of theaminophenylhalide, in mixture with the N-benzylidene aminophenylhalide,to the aminophenylacetylene, in mixture with the N-benzylidene3-aminophenylacetylene.

Example 4

Preparation of 3-aminophenylacetylene dimethylcarbinol: A mixture of3-bromoaniline (1.72 g, 10 mmol), 2-methyl-3-butyn-2-ol (1.1 g, 13mmol), benzaldehyde (0.3 g, 2.8 mmol, containing some benzoic acidimpurity), triethylamine (3 g), toluene (3 g),dichlorobis(triphenylphosphine)palladium (15 mg), and triphenylphosphine(80 mg) was deaerated by bubbling nitrogen and heated to 80° C. andtreated with Cul (10 mg). This mixture was refluxed for 7 hours. Thecooled reaction mixture was treated with aq NaOH (3 mL, 5 mM). Theaqueous phase was separated and the organic phase was distilled toremove TEA with more toluene being added. The resulting toluene solutionwas treated with aq HCl (5 mL, 9%). After 30 min the aqueous phase wasseparated and basified with 50% NaOH. The precipitated solid wasfiltered and dried to afford 1.2 g of 3-aminophenylacetylenedimethylcarbinol.

This example demonstrates that the N-benzylidene aminophenylhalide neednot be preformed ex situ, but can be formed in situ from theaminophenylhalide and the benzaldehyde, in this case substoichiometricbenzaldehyde containing benzoic acid impurity.

Example 5

Preparation of 3-aminophenylacetylene dimethylcarbinol: A mixture of3-bromoaniline (1.72 g, 10 mmol), 2-methyl-3-butyn-2-ol (1.1 g, 13mmol), 3-nitrobenzaldehyde (0.5 g, 3.3 mmol), triethylamine (5 g),dichlorobis(triphenylphosphine)palladium (15 mg) and triphenylphosphine(80 mg) was deaerated by bubbling nitrogen. The reaction mixture washeated to 80° C. and treated with CuI (10 mg). After 7 hr at refluxthin-layer chromatography showed nearly complete conversion of the3-bromoaniline to a mixture of 3-aminophenylacetylene dimethylcarbinoland N-(3-nitrobenzylidene) aminophenyl acetylene dimethylcarbinol.

This example demonstrates the use of another benzylidene group in theprocess of the invention, in this case 3-nitrobenzylidene provided by asubstoichiometric amount of 3-nitrobenzaldehyde with in situ formationof the N-(3-nitrobenzylidene) aminophenylhalide.

Example 6

Preparation of 3-aminodiphenylacetylene: A mixture of 3-bromoaniline(1.72 g, 10 mmol), benzaldehyde (0.27 g, 2.5 mmol, containing somebenzoic acid), and PdCl₂ (2 mg) in triethylamine (4 g) was deaerated bybubbling nitrogen. This mixture was refluxed for 45 min, then cooled to50° C. and treated with triphenylphosphine (73 mg in 0.8 gtriethylamine). Phenylacetylene (1.33 g, 13 mmol) and CuI (25 mg in 0.8g triethylamine) were then added. After refluxing for 6 hr, the reactionmixture was cooled and treated with water (5 mL). The triethylaminelayer was concentrated in vacuo and replaced by toluene. To thissolution was added aqueous HCl (15 mL, 7%). A precipitate was formed andit was filtered and washed with toluene. Drying in vacuo afforded3-aminodiphenylacetylene hydrochloride (1.4 g).

This example demonstrates another terminal acetylene in the process ofthe invention. Phenylacetylene is used to make anaminodiphenylacetylene.

Example 7

Preparation of 5-(4-aminophenyl)-4-pentyn-1-ol: A mixture of4-bromoaniline (1.72 g, 10 mmol), benzaldehyde (0.27 g, 2.5 mmol),benzoic acid (0.05 g, 0.4 mmol), PdCl₂ (2 mg) and triethylamine (3.5 g)was deaerated by bubbling nitrogen and then heated to reflux for 45 min.Thin-layer chromatography showed the formation of N-benzylidene4-aminophenylbromide). The reaction mixture was cooled to 50° C. andtreated with triphenylphosphine (73 mg in 1 g of triethylamine) followedby a slurry of CuI (20 mg) and 4-pentyn-1-ol (1.1 g, 13 mmol). Thisreaction mixture was heated at reflux for 10 hr. The mixture was cooledand diluted with triethylamine (5 mL) and treated with water (6 mL). Theaqueous layer was separated and the triethylamine layer was concentratedunder vacuum. Toluene was added and the mixture again concentrated. Thenaqueous HCl (10 mL, 7%) was added. The resulting aqueous solution wascooled, basified with 50% NaOH, and extracted with ethyl acetate. Theethyl acetate extract was evaporated under vacuum and the residue wasflash chromatographed (20% ethyl acetate-dichloromethane, silica) toyield 0.57 g of 5-(4-aminophenyl)-4-pentyn-1-ol as an oil.

This example demonstrates the use of another aminophenylhalide,4-bromoaniline, and another terminal acetylene, 4-pentyn-1-ol, in theprocess of the invention.

Example 8

Preparation of 3-aminophenylacetylene dimethylcarbinol: A mixture of3-bromoaniline (1.72 g, 10 mmol), 2-methyl-3-butyn-2-ol (1.1 g, 13 mmol)and benzaldehyde (0.3 g, 2.8 mmol, containing some benzoic acid) intriethylamine (5 g) was treated with palladium diacetate (11 mg) andtriphenylphosphine (197 mg). This mixture was deaerated by bubblingnitrogen and then heated to reflux. CuI (10 mg) was added and themixture was heated at reflux for 7 hours. Product isolation analogous toExample 2 gave 1.2 g of 3-aminophenylacetylene dimethylcarbinol.

This Example demonstrates the use of another palladium salt, palladiumdiacetate, to provide the palladium catalyst in the present invention.

The present invention has been shown by both description and examples.The Examples are only examples and cannot be construed to limit thescope of the invention. One of ordinary skill in the art will envisionequivalents to the inventive process described by the following claimswhich are within the scope and spirit of the claimed invention.

I claim as my invention:
 1. A process for the preparation of anN-arylmethylidene aminoarylacetylene comprising reacting aN-arylmethylidene aminoarylbromide with a terminal acetylene in thepresence of a base and a catalyst system comprising a palladium catalystand a cuprous salt.
 2. A process for the preparation of anaminoarylacetylene wherein the N-arylmethylidene aminoarylacetyleneproduced by the process of claim 1 is hydrolyzed to theaminoarylacetylene.
 3. The process of claim 1 wherein theN-arylmethylidene aminoarylbromide is provided in the reaction mixtureby reacting the corresponding arylcarboxaldehyde and the correspondingaminoarylbromide in the presence of an acid catalyst.
 4. The process ofclaim 3 wherein the acid catalyst is an arylcarboxylic acidcorresponding to the arylcarboxaldehyde present as an impurity in thearylcarboxaldehyde.
 5. The process of claim 1 wherein theN-arylmethylidene aminoarylbromide is a N-benzylidene aminophenylbromideand the N-arylmethylidene aminoarylacetylene is a N-benzylideneaminophenylacetylene.
 6. A process for the preparation of aaminophenylacetylene wherein the N-benzylidene aminophenylacetyleneproduced by the process of claim 5 is hydrolyzed to theaminophenylacetylene.
 7. The process of claim 5 wherein the terminalacetylene is an alpha-hydroxy terminal acetylene and the N-benzylideneaminophenylacetylene is a N-benzylidene aminophenylacetylene carbinol.8. The process of claim 7 wherein the alpha-hydroxy terminal acetyleneis acetylene dimethylcarbinol and the N-benzylidene aminophenylacetylenecarbinol is N-benzylidene aminophenylacetylene dimethylcarbinol.
 9. Theprocess of claim 8 wherein the N-benzylidene aminophenylbromide is anN-benzylidene 3-aminophenylbromide and the N-benzylideneaminophenylacetylene dimethylcarbinol is a N-benzylidene3-aminophenylacetylene dimethylcarbinol.
 10. The process of claim 5wherein the base comprises a trialkyl amine, wherein the palladiumcatalyst is selected from catalysts provided by palladium(0) compounds,catalysts provided by palladium(II) compounds, and catalysts provided bypalladium(II) salts and comprises a ligand wherein the ligating atom isselected from nitrogen and phosphorus, and wherein the cuprous salt is acuprous halide.
 11. A process for the preparation of anaminoarylacetylene comprising reacting a mixture of an aminoarylbromideand a corresponding N-arylmethylidene aminoarylbromide with a terminalacetylene in the presence of a base and a catalyst system comprising apalladium catalyst and a cuprous salt to provide a mixture of theaminoarylacetylene and the corresponding N-arylmethylideneaminoarylacetylene.
 12. The process of claim 11 further comprisinghydrolyzing the N-arylmethylidene aminoarylacetylene in the mixture tothe aminoarylacetylene.
 13. The process of claim 11 wherein theN-arylmethylidene aminoarylbromide is provided in the reaction mixtureby reacting a portion of the aminoarylbromide provided to the reactionwith a substoichiometric amount of the corresponding arylcarboxaldehydein the presence of an acid catalyst.
 14. The process of claim 13 whereinthe acid catalyst is an arylcarboxylic acid corresponding to thearylcarboxaldehyde present as an impurity in the arylcarboxaldehyde. 15.The process of claim 11 wherein the aminoarylbromide is anaminophenylbromide, the corresponding N-arylmethylidene aminoarylbromideis a N-benzylidene aminophenylbromide, the aminoarylacetylene is anaminophenylacetylene, and the corresponding N-arylmethylideneaminoarylacetylene is a N-benzylidene aminophenylacetylene.
 16. Theprocess of claim 15 further comprising hydrolyzing the N-benzylideneaminophenylacetylene in the mixture to the aminophenylacetylene.
 17. Theprocess of claim 15 wherein the terminal acetylene is an alpha-hydroxyterminal acetylene and the aminophenylacetylene is anaminophenylacetylene carbinol.
 18. The process of claim 17 wherein thealpha-hydroxy terminal acetylene is acetylene dimethylcarbinol and theaminophenylacetylene carbinol is an aminophenylacetylenedimethylcarbinol.
 19. The process of claim 18 wherein theaminophenylbromide is a 3-aminophenylbromide and theaminophenylacetylene dimethylcarbinol is 3-aminophenylacetylenedimethylcarbinol.
 20. The process of claim 15 wherein the base comprisesa trialkyl amine, wherein the palladium catalyst is selected fromcatalysts provided by palladium(0) compounds, catalysts provided bypalladium(II) compounds, and catalysts provided by palladium(II) saltsand comprises a ligand wherein the ligating atom is selected fromphosphorus and nitrogen, and wherein the cuprous salt is a cuproushalide.
 21. A process for the preparation of an aminophenylacetylenecomprising reacting an aminophenylbromide with a benzaldehyde to form aN-benzylidene aminophenylbromide, reacting the N-benzylideneaminophenylbromide with a terminal acetylene in the presence of a baseand a catalyst system comprising a palladium catalyst and a cuprous saltto form a N-benzylidene aminophenylacetylene, and subsequentlyhydrolyzing the N-benzylidene aminophenylacetylene to form theaminophenylacetylene.
 22. A process for the preparation of anaminophenylacetylene comprising reacting an aminophenylbromide with asubstoichiometric amount of a benzaldehyde to convert a correspondingamount of the aminophenylbromide to the corresponding N-benzylideneaminophenylbromide, reacting the mixture of the N-benzylideneaminophenylbromide and the remaining aminophenylbromide with a terminalacetylene in the presence of a base and a catalyst system comprising apalladium catalyst and a cuprous salt to form a product mixture of theaminophenylacetylene and the corresponding N-benzylideneaminophenylacetylene, and subsequently hydrolyzing the N-benzylideneaminophenylacetylene in the product mixture to the aminophenylacetylene.